Our project is an experimentally driven modeling effort to probe cell-cell communications among T lymphocytes in the adaptive immune system. T lymphocytes rely on cytokine communications to translate individual cell activation into collectively synchronized responses at the population level. Accordingly, regulatory T (Treg) cells are critical components of the immune response that can arbitrate every aspect of T cell activation (from antigen signaling to differentiation), through competition with effector T (Teff) cells for soluble cytokines. We conjecture that the buffering of cell-cell communication cytokines by Treg cells creates a dynamic hurdle that Teff cells must overcome to validate and pursue their own activation. We will test this conjecture with three projects. 1) We will model how regulation of long-term engagement of antigens through lymphocyte chemotaxis mediates antigen discrimination and clonal selection among Teff cells. 2) We will model how Treg cells compete for inflammatory cytokines upon which Teff cells rely, in order to collectively synchronize their activation status and differentiation. 3) We will design and test targeted manipulations of lymphocytes social interactions using fine- tuned cytokine delivery and blocking, as a promising method for immunotherapy. Our method combines quantitative in vitro and in vivo single-cell level characterization of T lymphocyte activation with biochemically explicit computational modeling. Our project will develop an experimentally validated quantitative model of cell-cell communications in the immune system to optimize targeted cytokine manipulations towards clinical applications. RELEVANCE: Perturbations of lymphocyte-lymphocyte communications through cytokine injection and blocking are promising avenues in the field of clinical immunotherapies. For this, quantitative approaches in immunology are required to model and harness the dynamic and combinatorial complexity of T cell activation. This project aims at building a quantitative framework to model and test varied perturbations of the balance between regulatory T cells and effector T cells in the immune system.